QUETIAPINE: 73,260 Adverse Event Reports & Safety Profile

Quetiapine is an atypical antipsychotic belonging to a chemical class, the dibenzothiazepine derivatives. The chemical designation is 2-[2-(4-dibenzo [ b,f ] [1,4] thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate (2:1) (salt). It is present in tablets as the fumarate salt. All doses and tablet strengths are expressed as milligrams of base, not as fumarate salt. Its molecular formula is C 42 H 50 N 6 O 4 S 2

• C 4 H 4 O 4 and it has a molecular weight of 883.11 (fumarate salt). The structural formula is: Quetiapine fumarate is a white to off-white crystalline powder which is moderately soluble in water. Quetiapine extended-release tablets, USP, are supplied for oral administration as 50 mg (pink), 150 mg (white), 200 mg (yellow), 300 mg (yellow) and 400 mg (white). All tablets are capsule shaped and film coated. Inactive ingredients for quetiapine extended-release tablets are hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium citrate. Inactive ingredients of the film coats are slightly different among the 5 strengths of tablets and are tabulated below: Strength Inactive ingredients of the film coat 50 mg polyvinyl alcohol-part. hydrolyzed, polyethylene glycol, titanium dioxide, talc, lecithin (soya) and Iron oxide red 150 mg polyvinyl alcohol-part. hydrolyzed, polyethylene glycol, titanium dioxide, talc and lecithin (soya) 200 mg polyvinyl alcohol-part. hydrolyzed, polyethylene glycol, titanium dioxide, talc, D&C Yellow #10 Aluminum Lake and Iron oxide red 300 mg polyvinyl alcohol-part. hydrolyzed, polyethylene glycol, titanium dioxide, talc and iron oxide yellow 400 mg polyvinyl alcohol-part. hydrolyzed, polyethylene glycol, titanium dioxide, talc and lecithin (soya)

Each

50 mg tablet contains 57.56 mg of quetiapine fumarate equivalent to 50 mg quetiapine.

Each

150 mg tablet contains 172.69 mg of quetiapine fumarate equivalent to 150 mg quetiapine.

Each

200 mg tablet contains 230.26 mg of quetiapine fumarate equivalent to 200 mg quetiapine.

Each

300 mg tablet contains 345.38 mg of quetiapine fumarate equivalent to 300 mg quetiapine.

Each

400 mg tablet contains 460.50 mg of quetiapine fumarate equivalent to 400 mg quetiapine. FDA approved dissolution test specifications differ from USP. structural formula

AND USAGE Quetiapine extended-release tablets is an atypical antipsychotic indicated for the treatment of:

• Schizophrenia (1.1)
• Bipolar I disorder, manic or mixed episodes (1.2)
• Bipolar disorder, depressive episodes (1.2)
• Major depressive disorder, adjunctive therapy with antidepressants (1.3)

1.1 Schizophrenia Quetiapine extended-release tablets is indicated for the treatment of schizophrenia. The efficacy of quetiapine extended-release tablets in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13 to 17 years) treated with quetiapine tablets <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>.

1.2 Bipolar Disorder Quetiapine extended-release tablets is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder, both as monotherapy and as an adjunct to lithium or divalproex. The efficacy of quetiapine extended-release tablets in manic or mixed episodes of bipolar I disorder was established in one 3-week trial in adults with manic or mixed episodes associated with bipolar I disorder. Efficacy was supported by two 12-week monotherapy trials and one 3-week adjunctive trial in adults with manic episodes associated with bipolar I disorder as well as one 3-week monotherapy trial in children and adolescents (10 to 17 years) with manic episodes associated with bipolar I disorder treated with quetiapine tablets <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>. Quetiapine extended-release tablets is indicated for the acute treatment of depressive episodes associated with bipolar disorder. The efficacy of quetiapine extended-release tablets was established in one 8-week trial in adults with bipolar I or II disorder and supported by two 8-week trials in adults with bipolar I or II disorder treated with quetiapine tablets <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>. Quetiapine extended-release tablets is indicated for the maintenance treatment of bipolar I disorder, as an adjunct to lithium or divalproex. Efficacy was extrapolated from two maintenance trials in adults with bipolar I disorder treated with quetiapine tablets. The effectiveness of monotherapy for the maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>.

1.3 Adjunctive Treatment of Major Depressive Disorder (MDD) Quetiapine extended-release tablets is indicated for use as adjunctive therapy to antidepressants for the treatment of MDD. The efficacy of quetiapine extended-release tablets as adjunctive therapy to antidepressants in MDD was established in two 6-week trials in adults with MDD who had an inadequate response to antidepressant treatment <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span>.

1.4 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder Pediatric schizophrenia and bipolar I disorder are serious mental disorders, however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment for both pediatric schizophrenia and bipolar I disorder is indicated as part of a total treatment program that often includes psychological, educational and social interventions.

1.1 Schizophrenia Quetiapine extended-release tablets is indicated for the treatment of schizophrenia. The efficacy of quetiapine extended-release tablets in schizophrenia was established in one 6-week and one maintenance trial in adults with schizophrenia. Efficacy was supported by three 6-week trials in adults with schizophrenia and one 6-week trial in adolescents with schizophrenia (13 to 17 years) treated with quetiapine tablets <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>.

2 DOSAGE & ADMINISTRATION

• Swallow tablets whole and do not split, chew or crush ( 2.1 )
• Take without food or with a light meal (approx. 300 calories) ( 2.1 )
• Administer once daily, preferably in the evening ( 2.1 )
• Geriatric Use: Consider a lower starting dose (50 mg/day), slower titration, and careful monitoring during the initial dosing period in the elderly. ( 2.3 , 8.5 )
• Hepatic Impairment: Lower starting dose (50 mg/day) and slower titration may be needed ( 2.4 , 8.7 , 12.3 )

Indication Initial Dose Recommended Dose

Maximum Dose Schizophrenia - Adults ( 2.2 ) 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia-Adolescents (13 to 17 years) ( 2.2 ) 50 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed - Acute monotherapy or adjunct to lithium or divalproex -Adults ( 2.2) 300 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic Acute monotherapy -Children and Adolescents (10 to 17 years) ( 2.2 ) 50 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes - Adults ( 2.2 ) 50 mg/day 300 mg/day 300 mg/day Major Depressive Disorder, Adjunctive Therapy with Antidepressants - Adults ( 2.2 ) 50 mg/day 150 to 300 mg/day 300 mg/day

2.1 Important Administration Instructions Quetiapine extended-release tablets should be swallowed whole and not split, chewed, or crushed. It is recommended that quetiapine extended-release tablets be taken without food or with a light meal (approximately 300 calories) [ see Clinical Pharmacology (12.3)]. Quetiapine extended-release tablets should be administered once daily, preferably in the evening.

2.2 Recommended Dosing The recommended initial dose, titration, dose range and maximum quetiapine extended-release tablets dose for each approved indication is displayed in Table 1 below. After initial dosing, adjustments can be made upwards or downwards, if necessary, depending upon the clinical response and tolerability of the patient <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 , 14.2 and 14.3 )]</span>.

Table

1: Recommended Dosing for Quetiapine Extended-Release Tablets Indication Initial Dose and Titration Recommended Dose Maximum Dose Schizophrenia -Adults Day 1: 300 mg/day Dose increases can be made at intervals as short as 1 day and in increments of up to 300 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia -Adolescents (13 to 17 years)

Day

1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 800 mg/day 800 mg/day Schizophrenia Maintenance - Monotherapy - Adults Not applicable 400 to 800 mg/day 800 mg/day Bipolar I Disorder manic or mixed - Acute monotherapy or adjunct to lithium or divalproex - Adults Day 1: 300 mg/day Day 2: 600 mg/day Day 3: between 400 and 800 mg/day 400 to 800 mg/day 800 mg/day Bipolar I Disorder, manic Acute monotherapy Children and Adolescents (10 to 17 years)

Day

1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day Day 5: 400 mg/day 400 to 600 mg/day 600 mg/day Bipolar Disorder, Depressive Episodes - Adults Day 1: 50 mg/day Day 2: 100 mg/day Day 3: 200 mg/day Day 4: 300 mg/day 300 mg/day 300 mg/day Bipolar I Disorder Maintenance - Adjunct to lithium or divalproex - Adults Not applicable 400 to 800 mg/day 800 mg/day Major Depressive Disorder - Adjunctive Therapy with Antidepressants-Adults Day 1: 50 mg/day Day 2: 50 mg/day Day 3: 150 mg/day 150 to 300 mg/day 300 mg/day Maintenance Treatment for Schizophrenia and Bipolar I Disorder Maintenance Treatment-Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [ see Clinical Studies ( 14.1 , 14.2 )].

2.3 Dose Modifications in Elderly Patients Consideration should be given to a slower rate of dose titration and a lower target dose in the elderly and in patients who are debilitated or who have a predisposition to hypotensive reactions <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 , 8.7 ), and Clinical Pharmacology ( 12.3 )]</span> . When indicated, dose escalation should be performed with caution in these patients. Elderly patients should be started on quetiapine extended-release tablets 50 mg/day and the dose can be increased in increments of 50 mg/day depending on the clinical response and tolerability of the individual patient.

2.4 Dose Modifications in Hepatically Impaired Patients Patients with hepatic impairment should be started on quetiapine extended-release tablets 50 mg/day. The dose can be increased daily in increments of 50 mg/day to an effective dose, depending on the clinical response and tolerability of the patient.

2.5 Dose Modifications when used with CYP3A4 Inhibitors Quetiapine extended-release tablets dose should be reduced to one-sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.). When the CYP3A4 inhibitor is discontinued, the dose of quetiapine extended-release tablets should be increased by 6-fold <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) and Drug Interactions ( 7.1 )]</span>.

2.6 Dose Modifications when used with CYP3A4 Inducers Quetiapine extended-release tablets dose should be increased up to 5-fold of the original dose when used in combination with a chronic treatment (e.g., greater than 7 to 14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). The dose should be titrated based on the clinical response and tolerance of the individual patient. When the CYP3A4 inducer is discontinued, the dose of quetiapine extended-release tablets should be reduced to the original level within 7 to 14 days <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) and Drug Interactions ( 7.1 )]</span>.

2.7 Re-initiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address re-initiation of treatment, it is recommended that when restarting therapy of patients who have been off quetiapine extended-release tablets for more than one-week, the initial dosing schedule should be followed. When restarting patients who have been off quetiapine extended-release tablets for less than one-week, gradual dose escalation may not be required and the maintenance dose may be re-initiated.

2.8 Switching Patients from Quetiapine Tablets to Quetiapine Extended-Release Tablets Patients who are currently being treated with quetiapine (immediate release formulation) may be switched to quetiapine extended-release tablets at the equivalent total daily dose taken once daily. Individual dosage adjustments may be necessary.

2.9 Switching from Antipsychotics There are no systematically collected data to specifically address switching patients from other antipsychotics to quetiapine extended-release tablets, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. When switching patients from depot antipsychotics, if medically appropriate, initiate quetiapine extended-release tablets therapy in place of the next scheduled injection. The need for continuing existing extrapyramidal syndrome medication should be re-evaluated periodically.

Hypersensitivity to quetiapine or to any excipients in the quetiapine extended-release tablets formulation. Anaphylactic reactions have been reported in patients treated with quetiapine extended-release tablets. Known hypersensitivity to quetiapine extended-release tablets or any components in the formulation. ( 4 )

REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: · Increased mortality in elderly patients with dementia-related psychosis [see Warning and Precautins (5.1)] · Suicidal thoughts and behaviors in adolescents and young adults [see Warning and Precautins (5.2)] · Cerebrovascular adverse reactions, including stroke in elderly patients with dementia-related psychosis [see Warning and Precautins (5.3)] · Neuroleptic Malignant Syndrome (NMS) [ see Warning and Precautins (5.4) ] · Metabolic changes (hyperglycemia, dyslipidemia, weight gain) [ see Warning and Precautins (5.5) ] · Tardive dyskinesia [ see Warning and Precautins (5.6) ] · Hypotension [ see Warning and Precautins (5.7) ]

• Falls [see Warnings and Precautions 5.8] · Increases in blood pressure (children and adolescents) [ see Warning and Precautins (5.9) ] · Leukopenia, neutropenia and agranulocytosis [ see Warning and Precautins (5.10) ] · Cataracts [ see Warning and Precautins (5.11) ] · QT Prolongation [ see Warning and Precautins (5.12) ] · Seizures [ see Warning and Precautins (5.13) ] · Hypothyroidism [ see Warning and Precautins (5.14) ] · Hyperprolactinemia[ see Warning and Precautins (5.15) ] · Potential for cognitive and motor impairment [ see Warning and Precautins (5.16) ] · Body temperature regulation[ see Warning and Precautins (5.17) ] · Dysphagia [ see Warning and Precautins (5.18) ] · Discontinuation Syndrome [ see Warning and Precautins (5.19) ]
• Most common adverse reactions (incidence ≥5% and twice placebo): Adults: somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, weight gain, lethargy, ALT increased, dyspepsia (6.1)
• Children and Adolescents: somnolence, dizziness, fatigue, increased appetite, nausea, vomiting, dry mouth, tachycardia, weight increased (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Study Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adults: The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 4300 patients. This database includes 698 patients exposed to quetiapine fumarate for the treatment of bipolar depression, 405 patients exposed to quetiapine fumarate for the treatment of acute bipolar mania (monotherapy and adjunct therapy), 646 patients exposed to quetiapine fumarate for the maintenance treatment of bipolar I disorder as adjunct therapy, and approximately 2600 patients and/or normal subjects exposed to 1 or more doses of quetiapine fumarate for the treatment of schizophrenia. Of these approximately 4300 subjects, approximately 4000 (2300 in schizophrenia, 405 in acute bipolar mania, 698 in bipolar depression, and 646 for the maintenance treatment of bipolar I disorder) were patients who participated in multiple dose effectiveness trials, and their experience corresponded to approximately 2400 patient-years. The conditions and duration of treatment with quetiapine fumarate varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed.

Adverse Reactions

Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: Overall, there was little difference in the incidence of discontinuation due to adverse reactions (4% for quetiapine fumarate vs. 3% for placebo) in a pool of controlled trials. However, discontinuations due to somnolence (0.8% quetiapine fumarate vs. 0% placebo) and hypotension (0.4% quetiapine fumarate vs. 0% placebo) were considered to be drug related [see Warnings and Precautions (5.7 and 5.19)].

Bipolar

Disorder: Mania: Overall, discontinuations due to adverse reactions were 5.7% for quetiapine fumarate vs. 5.1% for placebo in monotherapy and 3.6% for quetiapine fumarate vs. 5.9% for placebo in adjunct therapy. Depression: Overall, discontinuations due to adverse reactions were 12.3% for quetiapine fumarate 300 mg vs. 19% for quetiapine fumarate 600 mg and 5.2% for placebo.

Commonly Observed Adverse

Reactions in Short-Term, Placebo-Controlled Trials: In the acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) trials, the most commonly observed adverse reactions associated with the use of quetiapine fumarate monotherapy (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (18%), dizziness (11%), dry mouth (9%), constipation (8%), ALT increased (5%), weight gain (5%), and dyspepsia (5%).

Adverse Reactions

Occurring at an Incidence of 2% or More Among Quetiapine Fumarate Treated Patients in Short-Term, Placebo-Controlled Trials: The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied.

Table

9 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of schizophrenia (up to 6 weeks) and bipolar mania (up to 12 weeks) in 2% or more of patients treated with quetiapine fumarate (doses ranging from 75 to 800 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients.

Table

9: Adverse Reaction Incidence in 3- to 12-Week Placebo-Controlled Clinical Trials for the Treatment of Schizophrenia and Bipolar Mania (Monotherapy)

Preferred Term Quetiapine

Fumarate (n=719) PLACEBO (n=404)

Headache

21% 14% Agitation 20% 17% Somnolence 18% 8% Dizziness 11% 5% Dry Mouth 9% 3% Constipation 8% 3% Pain 7% 5% Tachycardia 6% 4% Vomiting 6% 5% Asthenia 5% 3% Dyspepsia 5% 1% Weight Gain 5% 1% ALT Increased 5% 1% Anxiety 4% 3% Pharyngitis 4% 3% Rash 4% 2% Abdominal Pain 4% 1% Postural Hypotension 4% 1% Back Pain 3% 1% AST Increased 3% 1% Rhinitis 3% 1% Fever 2% 1% Gastroenteritis 2% 0% Amblyopia 2% 1% In the acute adjunct therapy of bipolar mania (up to 3 weeks) studies, the most commonly observed adverse reactions associated with the use of quetiapine fumarate (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (34%), dry mouth (19%), asthenia (10%), constipation (10%), abdominal pain (7%), postural hypotension (7%), pharyngitis (6%), and weight gain (6%).

Table

10 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 3 weeks) of acute mania in 2% or more of patients treated with quetiapine fumarate (doses ranging from 100 to 800 mg/day) used as adjunct therapy to lithium and divalproex where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients.

Table

10: Adverse Reaction Incidence in 3-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Mania (Adjunct Therapy)

Preferred Term Quetiapine

Fumarate (n=196) PLACEBO (n=203)

Somnolence

34% 9% Dry Mouth 19% 3% Headache 17% 13% Asthenia 10% 4% Constipation 10% 5% Dizziness 9% 6% Tremor 8% 7% Abdominal Pain 7% 3% Postural Hypotension 7% 2% Agitation 6% 4% Weight Gain 6% 3% Pharyngitis 6% 3% Back Pain 5% 3% Hypertonia 4% 3% Rhinitis 4% 2% Peripheral Edema 4% 2% Twitching 4% 1% Dyspepsia 4% 3% Depression 3% 2% Amblyopia 3% 2% Speech Disorder 3% 1% Hypotension 3% 1% HormoneLevel Altered 3% 0% Heaviness 2% 1% Infection 2% 1% Fever 2% 1% Hypertension 2% 1% Tachycardia 2% 1% Increased Appetite 2% 1% Hypothyroidism 2% 1% Incoordination 2% 1% Thinking Abnormal 2% 0% Anxiety 2% 0% Ataxia 2% 0% Sinusitis 2% 1% Sweating 2% 1% Urinary Tract Infection 2% 1% In bipolar depression studies (up to 8 weeks), the most commonly observed treatment emergent adverse reactions associated with the use of quetiapine fumarate (incidence of 5% or greater) and observed at a rate on quetiapine fumarate at least twice that of placebo were somnolence (57%), dry mouth (44%), dizziness (18%), constipation (10%), and lethargy (5%).

Table

11 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during therapy (up to 8 weeks) of bipolar depression in 2% or more of patients treated with quetiapine fumarate (doses of 300 and 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. T able 11: Adverse Reaction Incidence in 8-Week Placebo-Controlled Clinical Trials for the Treatment of Bipolar Depression.

Preferred Term Quetiapine

Fumarate (n=698) PLACEBO (n=347)

Somnolence

3 57% 15% Dry Mouth 44% 13% Dizziness 18% 7% Constipation 10% 4% Fatigue 10% 8% Dyspepsia 7% 4% Vomiting 5% 4% Increased Appetite 5% 3% Lethargy 5% 2% Nasal Congestion 5% 3% Orthostatic Hypotension 4% 3% Akathisia 4% 1% Palpitations 4% 1% Vision Blurred 4% 2% Weight increased 4% 1% Arthralgia 3% 2% Paraesthesia 3% 2% Cough 3% 1% Extrapyramidal Disorder 3% 1% Irritability 3% 1% Dysarthria 3% 0% Hypersomnia 3% 0% Sinus Congestion 2% 1% Abnormal Dreams 2% 1% Tremor 2% 1% Gastroesophageal Reflux Disease 2% 1% Pain in Extremity 2% 1% Asthenia 2% 1% Balance Disorder 2% 1% Hypoesthesia 2% 1% Dysphagia 2% 0% Restless Legs Syndrome 2% 0% 3 Somnolence combines adverse reaction terms somnolence and sedation Explorations for interactions on the basis of gender, age, and race did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of these demographic factors.

Dose

Dependency of Adverse Reactions in Short-Term, Placebo-Controlled Trials Dose-related Adverse Reactions: Spontaneously elicited adverse reaction data from a study of schizophrenia comparing five fixed doses of quetiapine fumarate (75 mg, 150 mg, 300 mg, 600 mg, and 750 mg/day) to placebo were explored for dose-relatedness of adverse reactions. Logistic regression analyses revealed a positive dose response (p<0.05) for the following adverse reactions: dyspepsia, abdominal pain, and weight gain.

Adverse

Reactions in clinical trials with quetiapine and not listed elsewhere in the label: The following adverse reactions have also been reported with quetiapine: nightmares, hypersensitivity and elevations in serum creatine phosphokinase (not associated with NMS), galactorrhea, bradycardia (which may occur at or near initiation of treatment and be associated with hypotension and/ or syncope) decreased platelets, somnambulism (and other related events), elevations in gamma-GT levels, hypothermia, and priapism.

Extrapyramidal

Symptoms (EPS): Dystonia Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Four methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2)

Barnes Akathisia Rating

Scale (BARS)

Global Assessment

Score, (3) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (4) use of anticholinergic medications to treat emergent EPS. Adults: Data from one 6-week clinical trial of schizophrenia comparing five fixed doses of quetiapine fumarate (75, 150, 300, 600, 750 mg/day) provided evidence for the lack of treatment-emergent extrapyramidal symptoms (EPS) and dose-relatedness for EPS associated with quetiapine fumarate treatment. Three methods were used to measure EPS: (1) Simpson-Angus total score (mean change from baseline) which evaluates Parkinsonism and akathisia, (2) incidence of spontaneous complaints of EPS (akathisia, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor), and (3) use of anticholinergic medications to treat emergent EPS.

In Table

12, dystonic event included nuchal rigidity, hypertonia, dystonia, muscle rigidity, oculogyration; parkinsonism included cogwheel rigidity, tremor, drooling, hypokinesia; akathisia included akathisia, psychomotor agitation; dyskinetic event included tardive dyskinesia, dyskinesia, choreoathetosis; and other extrapyramidal event included restlessness, extrapyramidal disorder, movement disorder.

Table

12: Adverse Reactions Associated with EPS in a Short-Term, Placebo-Controlled Multiple Fixed-Dose Phase III Schizophrenia Trial (6 weeks duration)

Preferred Term Quetiapine Fumarate

75 mg/day (N=53)

Quetiapine Fumarate

150 mg/day (N=48)

Quetiapine Fumarate

300 mg/day (N=52)

Quetiapine Fumarate

600 mg/day (N=51)

Quetiapine Fumarate

750 mg/day (N=54) Placebo (N=51) n % n % n % n % n % n % Dystonic event 2 3.8 2 4.2 0 0 2 3.9 3 5.6 4

7.8 Parkinsonism 2 3.8 0 0 1 1.9 1 2 1 1.9 4

7.8 Akathisia 1 1.9 1 2.1 0 0 0 0 1 1.9 4

7.8 Dyskinetic event 2 3.8 0 0 0 0 1 2 0 0 0 0 Other extrapyramidal event 2 3.8 0 0 3 5.8 3 5.9 1 1.9 4

7.8 Parkinsonism incidence rates as measured by the Simpson-Angus total score for placebo and the five fixed doses (75, 150, 300, 600, 750 mg/day) were: -0.6; -1, -1.2; -1.6; -1.8 and -1.8. The rate of anticholinergic medication use to treat emergent EPS for placebo and the five fixed doses was: 14%; 11%; 10%; 8%; 12% and 11%. In six additional placebo-controlled clinical trials (3 in acute mania and 3 in schizophrenia) using variable doses of quetiapine fumarate, there were no differences between the quetiapine fumarate and placebo treatment groups in the incidence of EPS, as assessed by Simpson-Angus total scores, spontaneous complaints of EPS and the use of concomitant anticholinergic medications to treat EPS. In two placebo-controlled clinical trials for the treatment of bipolar depression using 300 mg and 600 mg of quetiapine fumarate, the incidence of adverse reactions potentially related to EPS was 12% in both dose groups and 6% in the placebo group. In these studies, the incidence of the individual adverse reactions (akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, muscle contractions involuntary, psychomotor hyperactivity and muscle rigidity) were generally low and did not exceed 4% in any treatment group.

The

3 treatment groups were similar in mean change in SAS total score and BARS Global Assessment score at the end of treatment. The use of concomitant anticholinergic medications was infrequent and similar across the three treatment groups. Children and Adolescents The information below is derived from a clinical trial database for quetiapine fumarate consisting of over 1000 pediatric patients. This database includes 677 patients exposed to quetiapine fumarate for the treatment of schizophrenia and 393 children and adolescents (10 to 17 years old) exposed to quetiapine fumarate for the treatment of acute bipolar mania.

Adverse Reactions

Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials Schizophrenia: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 8.2% and 2.7%, respectively. The adverse event leading to discontinuation in 1% or more of patients on quetiapine fumarate and at a greater incidence than placebo was somnolence (2.7% and 0% for placebo). Bipolar I Mania: The incidence of discontinuation due to adverse reactions for quetiapine-treated and placebo-treated patients was 11.4% and 4.4%, respectively. The adverse reactions leading to discontinuation in 2% or more of patients on quetiapine fumarate and at a greater incidence than placebo were somnolence (4.1% vs. 1.1%) and fatigue (2.1% vs. 0).

Commonly Observed Adverse

Reactions in Short-Term, Placebo-Controlled Trials In therapy for schizophrenia (up to 6 weeks), the most commonly observed adverse reactions associated with the use of quetiapine in adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (34%), dizziness (12%), dry mouth (7%), tachycardia ( 7%). In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%). In an acute (8-week) quetiapine fumarate extended-release tablets trial in children and adolescents (10 to17 years of age) with bipolar depression, in which efficacy was not established, the most commonly observed adverse reactions associated with the use of quetiapine fumarate extended-release tablets (incidence of 5% or greater and at least twice that for placebo) were dizziness 7%, diarrhea 5%, fatigue 5% and nausea 5%.

Adverse Reactions

Occurring at an Incidence of ≥2% among Quetiapine Fumarate Treated Patients in Short-Term, Placebo-Controlled Trials Schizophrenia (Adolescents, 13 to 17 years old) The following findings were based on a 6-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 800 mg/day.

Table

13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 6 weeks) of schizophrenia in 2% or more of patients treated with quetiapine fumarate (doses of 400 or 800 mg/day) where the incidence in patients treated with quetiapine fumarate was at least twice the incidence in placebo-treated patients. Adverse events that were potentially dose-related with higher frequency in the 800 mg group compared to the 400 mg group included dizziness (8% vs. 15%), dry mouth (4% vs. 10%), and tachycardia (6% vs. 11%).

Table

13: Adverse Reaction Incidence in a 6-Week Placebo-Controlled Clinical Trial for the Treatment of Schizophrenia in Adolescent Patients Preferred Term Quetiapine Fumarate 400 mg (n=73)

Quetiapine Fumarate

800 mg (n=74) Placebo (n=75)

Somnolence

1 33% 35% 11% Dizziness 8% 15% 5% Dry Mouth 4% 10% 1% Tachycardia 2 6% 11% 0% Irritability 3% 5% 0% Arthralgia 1% 3% 0% Asthenia 1% 3% 1% Back Pain 1% 3% 0% Dyspnea 0% 3% 0% Abdominal Pain 3% 1% 0% Anorexia 3% 1% 0% Tooth Abscess 3% 1% 0% Dyskinesia 3% 0% 0% Epistaxis 3% 0% 1% Muscle Rigidity 3% 0% 0% 1 Somnolence combines adverse reaction terms somnolence and sedation. 2 Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia. Bipolar I Mania (Children and Adolescents 10 to 17 years old) The following findings were based on a 3-week placebo-controlled trial in which quetiapine was administered in either doses of 400 or 600 mg/day.

Commonly Observed Adverse

Reactions In bipolar mania therapy (up to 3 weeks) the most commonly observed adverse reactions associated with the use of quetiapine in children and adolescents (incidence of 5% or greater and quetiapine incidence at least twice that for placebo) were somnolence (53%), dizziness (18%), fatigue (11%), increased appetite (9%), nausea (8%), vomiting (8%), tachycardia (7%), dry mouth (7%), and weight increased (6%).

Table

14 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during therapy (up to 3 weeks) of bipolar mania in 2% or more of patients treated with quetiapine fumarate (doses of 400 or 600 mg/day) where the incidence in patients treated with quetiapine fumarate was greater than the incidence in placebo-treated patients. Adverse events that were potentially dose-related with higher frequency in the 600 mg group compared to the 400 mg group included somnolence (50% vs. 57%), nausea (6% vs. 10%) and tachycardia (6% vs. 9%).

Table

14: Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial for the Treatment of Bipolar Mania in Children and Adolescent Patients Preferred Term Quetiapine Fumarate 400 mg (n=95)

Quetiapine Fumarate

600 mg (n=98) Placebo (n=90)

Somnolence

1 50% 57% 14% Dizziness 19% 17% 2% Nausea 6% 10% 4% Fatigue 14% 9% 4% Increased Appetite 10% 9% 1% Tachycardia 2 6% 9% 1% Dry Mouth 7% 7% 0% Vomiting 8% 7% 3% Nasal Congestion 3% 6% 2% Weight Increased 6% 6% 0% Irritability 3% 5% 1% Pyrexia 1% 4% 1% Aggression 1% 3% 0% Musculoskeletal Stiffness 1% 3% 1% Accidental Overdose 0% 2% 0% Acne 3% 2% 0% Arthralgia 4% 2% 1% Lethargy 2% 2% 0% Pallor 1% 2% 0% Stomach Discomfort 4% 2% 1% Syncope 2% 2% 0% Vision Blurred 3% 2% 0% Constipation 4% 2% 0% Ear Pain 2% 0% 0% Paraesthesia 2% 0% 0% Sinus Congestion 3% 0% 0% Thirst 2% 0% 0% 1 Somolence combines adverse reactions terms somnolence and sedation. 2 Tachycardia combines adverse reaction terms tachycardia and sinus tachycardia.

Extrapyramidal

Symptoms: In a short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration), the aggregated incidence of extrapyramidal symptoms was 12.9% (19/147) for quetiapine fumarate and 5.3% (4/75) for placebo, though the incidence of the individual adverse events (akathisia, tremor, extrapyramidal disorder, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group. In a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration), the aggregated incidence of extrapyramidal symptoms was 3.6% (7/193) or quetiapine fumarate and 1.1% (1/90) for placebo.

Table

15 presents a listing of patients with adverse reactions potentially associated with extrapyramidal symptoms in the short-term placebo-controlled monotherapy trial in adolescent patients with schizophrenia (6-week duration).

In Tables

15 – 16 dystonic event included nuchal rigidity, hypertonia, and muscle rigidity; parkinsonism included cogwheel rigidity and tremor; akathisia included akathisia only; dyskinetic event included tardive dyskinesia, dyskinesia, and choreoathetosis; and other extrapyramidal event included restlessness and extrapyramidal disorder.

Table

15: Adverse Reactions Associated with Extrapyramidal Symptoms in the Placebo-controlled Trial in Adolescent Patients with Schizophrenia (6-week duration)

Preferred Term Quetiapine Fumarate

400 mg/day (N=73)

Quetiapine Fumarate

800 mg/day (N=74)

All Quetiapine

Fumarate (N=147) Placebo (N=75) n % n % n % n % Dystonic event 2 2.7 0 0 2 1.4 0 0 Parkinsonism 4 5.5 4 5.4 8 5.4 2

2.7 Akathisia 3 4.1 4 5.4 7 4.8 3 4 Dyskinetic event 2 2.7 0 0 2 1.4 0 0 Other Extrapyramidal event 2 2.7 2 2.7 4 2.7 0 0 Table 16 presents a listing of patients with adverse reactions associated with extrapyramidal symptoms in a short-term placebo-controlled monotherapy trial in children and adolescent patients with bipolar mania (3-week duration).

Table

16: Adverse Reactions Associated with Extrapyramidal Symptoms in a Placebo-Controlled Trialin Children and Adolescent Patients with Bipolar I Mania (3-week duration)

Preferred Term

1 Quetiapine Fumarate 400 mg/day (N=95)

Quetiapine Fumarate

600 mg/day (N=98)

All Quetiapine

Fumarate (N=193) Placebo (N=90) n % n % n % n % Parkinsonism 2 2.1 1 1 3 1.6 1

1.1 Akathisia 1 1 1 1 2 1 0 0 Other Extrapyramidal event 1 1.1 1 1 2 1 0 0 1 There were no adverse experiences with the preferred term of dystonic or dyskinetic events.

Other Adverse Reactions Observed

During the Pre-Marketing Evaluation of Quetiapine Fumarate Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with quetiapine fumarate at multiple doses ≥ 75 mg/day during any phase of a trial within the premarketing database of approximately 2200 patients treated for schizophrenia. All reported reactions are included except those already listed in the tables or elsewhere in labeling, those reactions for which a drug cause was remote, and those reaction terms which were so general as to be uninformative. It is important to emphasize that, although the reactions reported occurred during treatment with quetiapine fumarate, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Nervous

System: Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased 2 , urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia; Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased 2 , neuralgia, stuttering, subdural hematoma. Body as a Whole: Frequent: flu syndrome; Infrequent: neck pain, pelvic pain 2 suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis; Rare: abdomen enlarged.

Digestive

System: Frequent: anorexia; Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema; Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis.

Cardiovascular

System: Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion; Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration.

Respiratory

System: Frequent: cough increased, dyspnea; Infrequent: pneumonia, epistaxis, asthma; Rare: hiccup, hyperventilation. Metabolic and Nutritional System: Infrequent: weight loss, alkaline phosphatase increased, hyperlipidemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia; Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication. Skin and Appendages System: Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer; Rare: exfoliative dermatitis, psoriasis, skin discoloration.

Urogenital

System: Infrequent: dysmenorrhea 2 , vaginitis 2 , urinary incontinence, metrorrhagia 2 , impotence 2 , dysuria, vaginal moniliasis 2 , abnormal ejaculation 2 , cystitis, urinary frequency, amenorrhea 2 , female lactation 2 , leukorrhea 2 , vaginal hemorrhage 2 , vulvovaginitis 2 , orchitis 2 ; Rare: gynecomastia 2 , nocturia, polyuria, acute kidney failure. _____________________________________ 2 Adjusted for gender Special Senses: Infrequent: conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain; Rare: abnormality of accommodation, deafness, glaucoma.

Musculoskeletal

System: Infrequent: pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain. Hemic and Lymphatic System: Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis; Rare: hemolysis, thrombocytopenia.

Endocrine

System: Infrequent: hypothyroidism, diabetes mellitus; Rare: hyperthyroidism. Laboratory, ECG and vital sign changes observed in clinical studies Laboratory Changes: Neutrophil Counts Adults : In placebo-controlled monotherapy clinical trials involving 3368 patients on quetiapine fumarate and 1515 on placebo, the incidence of at least one occurrence of neutrophil count <1x10 9 /L among patients with a normal baseline neutrophil count and at least one available follow up laboratory measurement was 0.3% (10/2967) in patients treated with quetiapine fumarate, compared to 0.1% (2/1349) in patients treated with placebo [see Warnings and Precautions (5.10)].

Transaminase Elevations

Adults : Asymptomatic, transient and reversible elevations in serum transaminases (primarily ALT) have been reported. In schizophrenia trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 6-week placebo-controlled trials were approximately 6% (29/483) for quetiapine fumarate compared to 1% (3/194) for placebo. In acute bipolar mania trials in adults, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in a pool of 3- to 12-week placebo-controlled trials were approximately 1% for both quetiapine fumarate (3/560) and placebo (3/294). These hepatic enzyme elevations usually occurred within the first 3 weeks of drug treatment and promptly returned to pre-study levels with ongoing treatment with quetiapine fumarate. In bipolar depression trials, the proportions of patients with transaminase elevations of >3 times the upper limits of the normal reference range in two 8-week placebo-controlled trials was 1% (5/698) for quetiapine fumarate and 2% (6/347) for placebo.

Decreased Hemoglobin

Adults : In short-term placebo-controlled trials, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 8.3% (594/7155) of quetiapine-treated patients compared to 6.2% (219/3536) of patients treated with placebo. In a database of controlled and uncontrolled clinical trials, decreases in hemoglobin to ≤13 g/dL males, ≤12 g/dL females on at least one occasion occurred in 11% (2277/20729) of quetiapine-treated patients. Interference with Urine Drug Screens There have been literature reports suggesting false positive results in urine enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. Caution should be exercised in the interpretation of positive urine drug screen results for these drugs, and confirmation by alternative analytical technique (e.g., chromatographic methods) should be considered.

Ecg

Changes Adults: Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant quetiapine fumarate/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. However, the proportions of patients meeting the criteria for tachycardia were compared in four 3- to 6-week placebo-controlled clinical trials for the treatment of schizophrenia revealing a 1% (4/399) incidence for quetiapine fumarate compared to 0.6% (1/156) incidence for placebo. In acute (monotherapy) bipolar mania trials the proportions of patients meeting the criteria for tachycardia was 0.5% (1/192) for quetiapine fumarate compared to 0% (0/178) incidence for placebo. In acute bipolar mania (adjunct) trials the proportions of patients meeting the same criteria was 0.6% (1/166) for quetiapine fumarate compared to 0% (0/171) incidence for placebo. In bipolar depression trials, no patients had heart rate increases to >120 beats per minute. quetiapine fumarate use was associated with a mean increase in heart rate, assessed by ECG, of 7 beats per minute compared to a mean increase of 1 beat per minute among placebo patients. This slight tendency to tachycardia in adults may be related to quetiapine fumarate's potential for inducing orthostatic changes [see Warnings and Precautions (5.7)] . Children and Adolescents: In the acute (6 week) schizophrenia trial in adolescents, increases in heart rate (>110 bpm) occurred in 5.2% (3/73) of patients receiving quetiapine fumarate 400 mg and 8.5% (5/74) of patients receiving quetiapine fumarate 800 mg compared to 0% (0/75) of patients receiving placebo. Mean increases in heart rate were 3.8 bpm and 11.2 bpm for quetiapine fumarate 400 mg and 800 mg groups, respectively, compared to a decrease of 3.3 bpm in the placebo group [see Warnings and Precautions (5.7)] . In the acute (3 week) bipolar mania trial in children and adolescents, increases in heart rate (>110 bpm) occurred in 1.1% (1/89) of patients receiving quetiapine fumarate 400 mg and 4.7% (4/85) of patients receiving quetiapine fumarate 600 mg compared to 0% (0/98) of patients receiving placebo. Mean increases in heart rate were 12.8 bpm and 13.4 bpm for quetiapine fumarate 400 mg and 600 mg groups, respectively, compared to a decrease of 1.7 bpm in the placebo group [see Warnings and Precautions (5.7)] . In an acute (8-week) quetiapine fumarate extended-release tablets trial in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, increases in heart rate (>110 bpm 10 to 12 years and 13 to 17 years) occurred in 0% of patients receiving quetiapine fumarate extended-release tablets and 1.2% of patients receiving placebo. Mean increases in heart rate were 3.4 bpm for quetiapine fumarate extended-release tablets, compared to 0.3 bpm in the placebo group [see Warnings and Precautions (5.7)] .

6.2 Postmarketing Experience The following adverse reactions were identified during post approval of quetiapine fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction which were temporally related to quetiapine therapy include anaphylactic reaction, cardiomyopathy, drug reaction with eosinophilia and systemic symptoms (DRESS), hyponatremia, myocarditis, nocturnal enuresis, pancreatitis, retrograde amnesia, rhabdomyolysis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).

AND PRECAUTIONS Cerebrovascular Adverse Reactions: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs (5.3)

Neuroleptic Malignant

Syndrome (NMS): Manage with immediate discontinuation and close monitoring (5.4)

Metabolic

Changes: Atypical antipsychotics have been associated with metabolic changes. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain (5.5) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically, during treatment Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended Tardive Dyskinesia: Discontinue if clinically appropriate (5.6) Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease (5.7)

Increased Blood

Pressure in Children and Adolescents: Monitor blood pressure at the beginning of, and periodically during treatment in children and adolescents (5.9) Leukopenia, Neutropenia and Agranulocytosis: Monitor complete blood count frequently during the first few months of treatment in patients with a pre-existing low white cell count or a history of leukopenia/neutropenia and discontinue quetiapine extended-release tablets at the first sign of a decline in WBC in absence of other causative factors (5.10) Cataracts: Lens changes have been observed in patients during long-term quetiapine treatment. Lens examination is recommended when starting treatment and at 6-month intervals during chronic treatment (5.11) Anticholinergic (antimuscarinic) Effects: Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy or constipation (5.20).

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Quetiapine

Extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.

Table

2: Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and non-psychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for quetiapine extended-release tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening

Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, including quetiapine extended-release tablets, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects.

Quetiapine

Extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ].

5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these metabolic profiles should be managed as clinically appropriate. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Adults: Table 3: Fasting Glucose—Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤ 12 weeks) Placebo-Controlled Studies 1 Laboratory Analyte Category Change (At Least Once) from Baseline Treatment Arm N Patients n (%)

Fasting Glucose

Normal to High (<100 mg/dL to ≥126 mg/dL)

Quetiapine

2907 71 (2.4%)

Placebo

1346 19 (1.4%) Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)

Quetiapine

572 67 (11.7%)

Placebo

279 33 (11.8%) 1 Includes quetiapine tablets and quetiapine extended-release tablets data. In a 24-week trial (active-controlled, 115 patients treated with quetiapine tablets) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting blood glucose level ≥ 126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2-hour glucose from baseline was -1.8 mg/dL for quetiapine.

In

2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for quetiapine tablets (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and –0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine tablets (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).

Table

4 shows the percentage of patients with shifts in blood glucose to ≥ 126 mg/dL from normal baseline in MDD adjunct therapy trials by dose.

Table

4: Percentage of Patients with Shifts from Normal Baseline in Blood Glucose to ≥ 126 mg/dL (assumed fasting) in MDD Adjunct Therapy Trials by Dose Laboratory Analyte Treatment Arm N Patients n (%)

Blood

Glucose ≥ 126 mg/dL Quetiapine Extended-release tablets 150 mg 280 19 (7%)

Quetiapine

Extended-release tablets 300 mg 269 32 (12%)

Placebo

277 17 (6%) Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets are supported from studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.2)]. In a placebo-controlled quetiapine extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for quetiapine extended-release tablets (n = 60) compared to placebo (n = 62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the quetiapine extended-release tablets or placebo-treated groups with a baseline normal fasting glucose level (< 100 mg/dL) that had an increase in blood glucose level ≥ 126 mg/dL. There was one patient in the quetiapine extended-release tablets group with a baseline borderline fasting glucose level (≥ 100 mg/dL) and < 126 mg/dL) who had an increase in blood glucose level of > 126 mg/dL compared to zero patients in the placebo group. In a placebo-controlled quetiapine tablets monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine tablets (n=138) compared to placebo (n=67) was –0.75 mg/dL versus –1.70 mg/dL. In a placebo-controlled quetiapine tablets monotherapy study of children and adolescent patients (10 to 17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine tablets (n=170) compared to placebo (n=81) was 3.62 mg/dL versus –1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥100 mg/dL and <126 mg/dL) had a blood glucose level of ≥126 mg/dL.

Dyslipidemia

Adults: Table 5 shows the percentage of patients with changes in cholesterol and triglycerides from baseline by indication in clinical trials with quetiapine extended-release tablets.

Table

5: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%)

Total

Cholesterol ≥240 mg/dL Schizophrenia 1 Quetiapine Extended-release tablets 718 67 (9%)

Placebo

232 21 (9%)

Bipolar Depression

2 Quetiapine Extended-release tablets 85 6 (7%)

Placebo

106 3 (3%)

Bipolar Mania

3 Quetiapine Extended-release tablets 128 9 (7%)

Placebo

134 5 (4%)

Major Depressive

Disorder (Adjunct Therapy) 1 Quetiapine Extended-release tablets 420 67 (16%)

Placebo

213 15 (7%) Triglycerides ≥200 mg/dL Schizophrenia 1 Quetiapine Extended-release tablets 659 118 (18%)

Placebo

214 11 (5%)

Bipolar Depression

2 Quetiapine Extended-release tablets 84 7 (8%)

Placebo

93 7 (8%)

Bipolar Mania

3 Quetiapine Extended-release tablets 102 15 (15%)

Placebo

125 8 (6%)

Major Depressive

Disorder (Adjunct Therapy) 1 Quetiapine Extended-release tablets 458 75 (16%)

Placebo

223 18 (8%) LDL-Cholesterol ≥ 160 mg/dL Schizophrenia 1 Quetiapine Extended-release tablets 691 47 (7%)

Placebo

227 17 (8%)

Bipolar Depression

2 Quetiapine Extended-release tablets 86 3 (4%)

Placebo

104 2 (2%)

Bipolar Mania

3 Quetiapine Extended-release tablets 125 5 (4%)

Placebo

135 2 (2%)

Major Depressive

Disorder (Adjunct Therapy) 1 Quetiapine Extended-release tablets 457 51 (11%)

Placebo

219 21 (10%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia 1 Quetiapine Extended-release tablets 600 87 (15%)

Placebo

195 23 (12%)

Bipolar Depression

2 Quetiapine Extended-release tablets 78 7 (9%)

Placebo

83 6 (7%)

Bipolar Mania

3 Quetiapine Extended-release tablets 100 19 (19%)

Placebo

115 15 (13%)

Major Depressive

Disorder (Adjunct Therapy) 1 Quetiapine Extended-release tablets 470 34 (7%)

Placebo

230 19 (8%) 1 6 weeks duration 2 8 weeks duration 3 3 weeks duration In quetiapine tablets clinical trials for schizophrenia, the percentage of patients with shifts in cholesterol and triglycerides from baseline to clinically significant levels were 18% (placebo: 7%) and 22% (placebo: 16%). HDL-cholesterol and LDL-cholesterol parameters were not measured in these studies. In quetiapine tablets clinical trials for bipolar depression, the following percentage of patients had shifts from baseline to clinically significant levels for the four lipid parameters measured: total cholesterol 9% (placebo: 6%); triglycerides 14% (placebo: 9%); LDL-cholesterol 6% (placebo: 5%) and HDL-cholesterol 14% (placebo: 14%). Lipid parameters were not measured in the bipolar mania studies.

Table

6 shows the percentage of patients in MDD adjunctive therapy trials with clinically significant shifts in total-cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline by dose.

Table

6: Percentage of Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels in MDD Adjunctive Therapy Trials by Dose Laboratory Analyte Treatment Arm 1 N Patients n (%) Cholesterol ≥ 240 mg/dL Quetiapine Extended-release tablets 150 mg 223 41 (18%)

Quetiapine

Extended-release tablets 300 mg 197 26 (13%)

Placebo

213 15 (7%) Triglycerides ≥ 200 mg/dL Quetiapine Extended-release tablets 150 mg 232 36 (16%)

Quetiapine

Extended-release tablets 300 mg 226 39 (17%)

Placebo

223 18 (8%) LDL-Cholesterol ≥ 160 mg/dL Quetiapine Extended-release tablets 150 mg 242 29 (12%)

Quetiapine

Extended-release tablets 300 mg 215 22 (10%)

Placebo

219 21 (10%) HDL-Cholesterol ≤ 40 mg/dL Quetiapine Extended-release tablets 150 mg 238 14 (6%)

Quetiapine

Extended-release tablets 300 mg 232 20 (9%)

Placebo

230 19 (8%) 1 6 weeks duration Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies ( 14.1 and 14.2 )]. In a placebo-controlled quetiapine extended-release tablets monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥ 130 mg/dL) and HDL-cholesterol (≤40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for quetiapine extended-release tablets vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for quetiapine extended-release tablets vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for quetiapine extended-release tablets vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for quetiapine extended-release tablets vs. 15% (11/74) for placebo.

Table

7 shows the percentage of children and adolescents with shifts in total cholesterol, triglycerides, LDL-cholesterol, and HDL-cholesterol from baseline to clinically significant levels by indication in clinical trials with quetiapine tablets in adolescents (13 to 17 years) with schizophrenia and in children and adolescents (10 to 17 years) with bipolar mania.

Table

7: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol, and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication Laboratory Analyte Indication Treatment Arm N Patients n (%)

Total

Cholesterol ≥200 mg/dL Schizophrenia 1 Quetiapine Tablets 107 13 (12%)

Placebo

56 1 (2%)

Bipolar Mania

2 Quetiapine Tablets 159 16 (10%)

Placebo

66 2 (3%) Triglycerides ≥150 mg/dL Schizophrenia 1 Quetiapine Tablets 103 17 (17%)

Placebo

51 4 (8%)

Bipolar Mania

2 Quetiapine Tablets 149 32 (22%)

Placebo

60 8 (13%) LDL-Cholesterol ≥ 130 mg/dL Schizophrenia 1 Quetiapine Tablets 112 4 (4%)

Placebo

60 1 (2%)

Bipolar Mania

2 Quetiapine Tablets 169 13 (8%)

Placebo

74 4 (5%) HDL-Cholesterol ≤ 40 mg/dL Schizophrenia 1 Quetiapine Tablets 104 16 (15%)

Placebo

54 10 (19%)

Bipolar Mania

2 Quetiapine Tablets 154 16 (10%)

Placebo

61 4 (7%) 1 13 to 17 years, 6 weeks duration 2 10 to 17 years, 3 weeks duration Weight Gain Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight. Adults: Table 8 shows the percentage of adult patients with weight gain of ≥7% of body weight by indication.

Table

8: Percentage of Patients with Weight Gain ≥7% of Body Weight (Adults) by Indication Vital sign Indication Treatment Arm N Patients n (%) Weight gain ≥7% of Body Weight Schizophrenia 1 Quetiapine Extended-release tablets 907 90 (10%)

Placebo

299 16 (5%)

Bipolar Mania

2 Quetiapine Extended-release tablets 138 7 (5%)

Placebo

150 0 (0%)

Bipolar Depression

3 Quetiapine Extended-release tablets 110 9 (8%)

Placebo

125 1 (1%)

Major Depressive

Disorder (Adjunctive Therapy) 1 Quetiapine Extended-release tablets 616 32 (5%)

Placebo

302 5 (2%) 1 6 weeks duration 2 3 weeks duration 3 8 weeks duration In schizophrenia trials, the proportions of patients meeting a weight gain criterion of ≥7% of body weight were compared in a pool of four 3- to 6-week placebo-controlled clinical trials, revealing a statistically significant greater incidence of weight gain for quetiapine tablets (23%) compared to placebo (6%).

Table

9 shows the percentage of adult patients with weight gain of ≥7% of body weight for MDD by dose.

Table

9: Percentage of Patients with Weight Gain ≥7% of Body Weight in MDD Adjunctive Therapy Trials by Dose (Adults) Vital sign Treatment Arm N Patients n (%)

Weight

Gain ≥7% of Body Weight in MDD Adjunctive Therapy Quetiapine Extended-release tablets 150 mg 309 10 (3%)

Quetiapine

Extended-release tablets 300 mg 307 22 (7%)

Placebo

302 5 (2%) Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies (14.1 and 14.2)]. In a clinical trial for quetiapine extended-release tablets in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥7% of body weight at any time was 15% (14/92) for quetiapine extended-release tablets vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the quetiapine extended-release tablets group vs. 0.6 kg in the placebo group. Weight gain was greater in patients 10 to 12 years of age compared to patients 13 to 17 years of age. The percentage of patients 10 to 12 years of age with weight gain ≥7% at any time was 28% (7/25) for quetiapine extended-release tablets vs. 0% (0/28) for placebo. The percentage of patients 13 to 17 years of age with weight gain ≥7% at any time was 10.4% (7/67) for quetiapine extended-release tablets vs. 13.9% (10/72) for placebo.

Table

10 shows the percentage of children and adolescents with weight gain ≥7% of body weight in clinical trials with quetiapine tablets in adolescents (13 to 17 years) with schizophrenia and in children and adolescents (10 to 17 years) with bipolar mania.

Table

10: Percentage of Patients with Weight Gain ≥7% of Body Weight (Children and Adolescents) Vital sign Indication Treatment Arm N Patients n (%) Weight gain ≥7% of Body Weight Schizophrenia 1 Quetiapine Tablets 111 23 (21%)

Placebo

44 3 (7%)

Bipolar Mania

2 Quetiapine Tablets 157 18 (12%)

Placebo

68 0 (0%) 1 6 weeks duration 2 3 weeks duration The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine tablets group and -0.4 kg in the placebo group and in the bipolar mania trial it was 1.7 kg in the quetiapine tablets group and 0.4 kg in the placebo group. In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine tablets.

After

26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on quetiapine tablets met this criterion after 26 weeks of treatment. When treating pediatric patients with quetiapine tablets for any indication, weight gain should be assessed against that expected for normal growth.

5.6 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, quetiapine extended-release tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. Given these considerations, quetiapine extended-release tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.If signs and symptoms of tardive dyskinesia appear in a patient on quetiapine extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with quetiapine despite the presence of the syndrome.

5.7 Hypotension Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its ά1-adrenergic antagonist properties. Syncope was reported in 0.3% (5/1866) of the patients treated with quetiapine extended-release tablets across all indications, compared with 0.2% (2/928) on placebo. Syncope was reported in 1% (28/3265) of the patients treated with quetiapine tablets, compared with 0.2% (2/954) on placebo. Orthostatic hypotension, dizziness, and syncope may lead to falls. Quetiapine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate.

5.8 Falls Atypical antipsychotic drugs, including quetiapine extended-release tablets, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Increases in Blood Pressure (Children and Adolescents) Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 and 14.2 )]</span>. In a placebo-controlled quetiapine extended-release tablets clinical trial (8 weeks duration) in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 6.5% (6/92) for quetiapine extended-release tablets and 6.0% (6/100) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 46.7% (43/92) for quetiapine extended-release tablets and 36.0% (36/100) for placebo. In placebo-controlled trials in children and adolescents with schizophrenia (13 to 17 years old, 6-week duration) or bipolar mania (10 to 17 years old, 3-week duration), the incidence of increases at any time in systolic blood pressure (≥20 mmHg) was 15.2% (51/335) for quetiapine tablets and 5.5% (9/163) for placebo; the incidence of increases at any time in diastolic blood pressure (≥10 mmHg) was 40.6% (136/335) for quetiapine tablets and 24.5% (40/163) for placebo. In the 26-week open-label clinical trial, one child with a reported history of hypertension experienced a hypertensive crisis. Blood pressure in children and adolescents should be measured at the beginning of, and periodically during treatment.

5.10 Leukopenia, Neutropenia, and Agranulocytosiss In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine. Agranulocytosis has also been reported.In clinical trials and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to atypical antipsychotic agents, including quetiapine. Agranulocytosis has also been reported. Agranulocytosis has been reported with quetiapine, including fatal cases and cases in patients without pre-existing risk factors. Neutropenia should be considered in patients presenting with infection, particularly in the absence of obvious predisposing factor(s), or in patients with unexplained fever, and should be managed as clinically appropriate. Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine extended-release tablets at the first sign of a decline in WBC in absence of other causative factors.Possible risk factors for leukopenia/neutropenia include pre-existing low white cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue quetiapine extended-release tablets at the first sign of a decline in WBC in absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count &lt;1000/mm) should discontinue quetiapine extended-release tablets and have their WBC followed until recovery. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count &lt;1000/mm 3 ) should discontinue quetiapine extended-release tablets and have their WBC followed until recovery.

5.11 Cataracts The development of cataracts was observed in association with quetiapine treatment in chronic dog studies <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.2) ]</span>. Lens changes have also been observed in adults, children, and adolescents during long-term quetiapine treatment but a causal relationship to quetiapine use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment.

5.12 QT Prolongation In clinical trials quetiapine was not associated with a persistent increase in QT intervals. However, the QT effect was not systematically evaluated in a thorough QT study. In post marketing experience there were cases reported of QT prolongation in patients who overdosed on quetiapine <span class="opacity-50 text-xs">[see Overdosage (10.1) ]</span> , in patients with concomitant illness, and in patients taking medicines known to cause electrolyte imbalance or increase QT interval. The use of quetiapine should be avoided in combination with other drugs that are known to prolong QTc including Class 1A antiarrythmics (e.g., quinidine, procainamide) or Class III antiarrythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). Quetiapine should also be avoided in circumstances that may increase the risk of occurrence of torsade de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. Caution should also be exercised when quetiapine is prescribed in patients with increased risk of QT prolongation (e.g., cardiovascular disease, family history of QT prolongation, the elderly, congestive heart failure and heart hypertrophy).

5.13 Seizures During short-term clinical trials with quetiapine extended-release tablets, seizures occurred in 0.05% (1/1866) of patients treated with quetiapine extended-release tablets across all indications compared to 0.3% (3/928) on placebo. During clinical trials with quetiapine tablets, seizures occurred in 0.5% (20/3490) of patients treated with quetiapine tablets compared to 0.2% (2/954) on placebo. As with other antipsychotics, quetiapine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

5.14 Hypothyroidism Adults: Clinical trials with quetiapine demonstrated dose-related decreases in thyroid hormone levels. The reduction in total and free thyroxine (T 4 ) of approximately 20% at the higher end of the therapeutic dose range was maximal in the first six weeks of treatment and maintained without adaptation or progression during more chronic therapy. In nearly all cases, cessation of quetiapine treatment was associated with a reversal of the effects on total and free T 4 , irrespective of the duration of treatment. The mechanism by which quetiapine effects the thyroid axis is unclear. If there is an effect on the hypothalamic-pituitary axis, measurement of TSH alone may not accurately reflect a patient’s thyroid status. Therefore, both TSH and free T 4 , in addition to clinical assessment, should be measured at baseline and at follow-up. In quetiapine extended-release tablets clinical trials across all indications 1.8% (24/1336) of patients on quetiapine extended-release tablets versus 0.6% (3/530) on placebo experienced decreased free thyroxine (&lt;0.8 LLN) and 1.6% (21/1346) on quetiapine extended-release tablets vs. 3.4% (18/534) on placebo experienced increased thyroid stimulating hormone (TSH).

About

0.7% (26/3489) of quetiapine tablets patients did experience TSH increases in monotherapy studies. Some patients with TSH increases needed replacement thyroid treatment. In all quetiapine trials, the incidence of shifts in thyroid hormones and TSH were : decrease in free T 4 (<0.8 LLN), 2.0% (357/17513); decrease in total T 4 (<0.8 LLN), 4.0% (75/1861); decrease in free T 3 (<0.8 LLN), 0.4% (53/13766); decrease in total T 3 (<0.8 LLN), 2.0% (26/1312), and increase in TSH(>5 mIU/L), 4.9% (956/19412). In eight patients, where TBG was measured, levels of TBG were unchanged.

Table

11 shows the incidence of these shifts in short term placebo-controlled clinical trials.

Table

11 : Incidence of Shifts in Thyroid Hormone Levels and TSH in Short Term Placebo-Controlled Clinical Trials 1, 2 Total T4 Free T4 Total T3 Free T3 TSH Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo Quetiapine Placebo 3.4% (37/1097) 0.6% (4/651) 0.7% (52/7218) 0.1% (4/3668) 0.5% (2/369) 0.0% (0/113) 0.2% (11/5673) 0.0% (1/2679) 3.2% (240/7587) 2.7% (105/3912) 1 Based on shifts from normal baseline to potentially clinically important value at any time post-baseline. Shifts in total T 4 , free T 4 , total T 3 and free T 3 are defined as <0.8 x LLN (pmol/L) and shift in TSH is > 5 mIU/L at any time. 2 Includes quetiapine tablets and quetiapine extended-release tablets data. In short-term placebo-controlled monotherapy trials, the incidence of reciprocal shifts in T 3 and TSH was 0.0 % for both quetiapine (1/4800) and placebo (0/2190) and for T 4 and TSH the shifts were 0.1% (7/6154) for quetiapine versus 0.0 % (1/3007) for placebo. Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age [see Clinical Studies ( 14.1 and 14.2) ]. In acute placebo-controlled trials in children and adolescent patients with schizophrenia (6-week duration) or bipolar mania (3-week duration), the incidence of shifts at any time for quetiapine tablets treated patients and placebo-treated patients for elevated TSH was 2.9% (8/280) vs. 0.7% (1/138), respectively and for decreased total thyroxine was 2.8% (8/289) vs. 0% (0/145), respectively. Of the quetiapine tablets treated patients with elevated TSH levels, 1 had simultaneous low free T 4 level at end of treatment.

5.15 Hyperprolactinemia Adults : During clinical trials with quetiapine across all indications, the incidence of shifts in prolactin levels to a clinically significant value occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968) on placebo. Children and Adolescents: Safety and effectiveness of quetiapine extended-release tablets are supported by studies of quetiapine tablets in children and adolescent patients 10 to 17 years of age <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 and 14.2 )]</span>. In acute placebo-controlled trials in children and adolescent patients with bipolar mania (3-week duration) or schizophrenia (6-week duration), the incidence of shifts in prolactin levels to a value (&gt;20 µg/L males; &gt; 26 µg/L females at any time) was 13.4% (18/134) for quetiapine tablets compared to 4% (3/75) for placebo in males and 8.7% (9/104) for quetiapine tablets compared to 0% (0/39) for placebo in females. Like other drugs that antagonize dopamine D2 receptors, quetiapine extended-release tablets elevates prolactin levels in some patients and the elevation may persist during chronic administration. Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in carcinogenicity studies conducted in mice and rats <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.1) ]</span>. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

5.16 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction reported in patients treated with quetiapine especially during the 3-day period of initial dose titration. In schizophrenia trials, somnolence was reported in 24.7% (235/951) of patients on quetiapine extended-release tablets compared to 10.3% (33/319) of placebo patients. In a bipolar depression clinical trial, somnolence was reported in 51.8% (71/137) of patients on quetiapine extended-release tablets compared to 12.9% (18/140) of placebo patients. In a clinical trial for bipolar mania, somnolence was reported in 50.3% (76/151) of patients on quetiapine extended-release tablets compared to 11.9% (19/160) of placebo patients. Since quetiapine has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably certain that quetiapine therapy does not affect them adversely. Somnolence may lead to falls. In short-term adjunctive therapy trials for MDD, somnolence was reported in 40% (252/627) of patients on quetiapine extended-release tablets respectively compared to 9% (27/309) of placebo patients. Somnolence was dose-related in these trials (37% (117/315) and 43% (135/312) for the 150 mg and 300 mg groups, respectively).

5.17 Body Temperature Regulation Disruption of the body&apos;s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing quetiapine extended-release tablets for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.18 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer&apos;s dementia. Quetiapine extended-release tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.19 Discontinuation Syndrome Acute withdrawal symptoms, such as insomnia, nausea, and vomiting have been described after abrupt cessation of atypical antipsychotic drugs, including quetiapine. In short-term placebo-controlled, monotherapy clinical trials with quetiapine extended-release tablets that included a discontinuation phase which evaluated discontinuation symptoms, the aggregated incidence of patients experiencing one or more discontinuation symptoms after abrupt cessation was 12.1% (241/1993) for quetiapine extended-release tablets and 6.7% (71/1065) for placebo. The incidence of the individual adverse reactions (i.e., insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability) did not exceed 5.3% in any treatment group and usually resolved after 1-week post-discontinuation. Gradual dose reduction is advised. <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>

5.20 Anticholinergic (antimuscarinic)

Effects

Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine is used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects. Norquetiapine, an active metabolite of quetiapine, has moderate to strong affinity for several muscarinic receptor subtypes. This contributes to anticholinergic adverse reactions when quetiapine is used at therapeutic doses, taken concomitantly with other anticholinergic medications, or taken in overdose. Quetiapine should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Drug Interactions (7.1) , Overdosage (10.1) , and Clinical Pharmacology (12.1)] . Constipation was a commonly reported adverse event in patients treated with quetiapine and represents a risk factor for intestinal obstruction. Intestinal obstruction has been reported with quetiapine, including fatal reports in patients who were receiving multiple concomitant medications that decrease intestinal motility. Quetiapine should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, or constipation.

INTERACTIONS

• Concomitant use of strong: CYP3A4 inhibitors Reduce quetiapine dose to one-sixth when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) ( 2.5 , 7.1 , 12.3 )
• Concomitant use of strong CYP3A4 inducers: Increase quetiapine dose up to 5 fold when used in combination with a chronic treatment (more than 7 to 14 days) of potent CYP3A4 inducers (e.g., phenytoin, rifampin, St. John’s wort) ( 2.6 , 7.1 , 12.3 )
• Discontinuation of strong CYP3A4 inducers: Reduce quetiapine dose by 5-fold within 7 to 14 days of discontinuation of CYP3A4 inducers ( 2.6 , 7.1 , 12.3 )

7.1 Effect of Other Drugs on Quetiapine The risks of using quetiapine extended-release tablets in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of quetiapine extended-release tablets, caution should be used when it is taken in combination with other centrally acting drugs. Quetiapine potentiated the cognitive and motor effects of alcohol in a clinical trial in subjects with selected psychotic disorders, and alcoholic beverages should be limited while taking quetiapine. Quetiapine exposure is increased by the prototype CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, indinavir, ritonavir, nefazodone, etc.) and decreased by the prototype of CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, avasimibe, St. John’s wort etc.). Dose adjustment of quetiapine will be necessary if it is co-administered with potent CYP3A4 inducers or inhibitors. CYP3A4 inhibitors: Coadministration of ketoconazole, a potent inhibitor of cytochrome CYP3A4, resulted in significant increase in quetiapine exposure. The dose should be reduced to one-sixth of the original dose in patients coadministered with a strong CYP3A4 inhibitor <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]</span>. CYP3A4 inducers: Coadministration of quetiapine and phenytoin, a CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold. Increased doses of quetiapine extended-release tablets up to 5-fold may be required to maintain control of symptoms of schizophrenia in patients receiving quetiapine and phenytoin, or other known potent CYP3A4 inducers <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ]</span>. When the CYP3A4 inducer is discontinued, the dose of quetiapine extended-release tablets should be reduced to the original level within 7 to 14 days <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span>.

Anticholinergic

Drugs: Concomitant treatment with quetiapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Quetiapine extended-release tablets should be used with caution in patients receiving medications having anticholinergic (antimuscarinic) effects [see Warnings and Precautions (5.20)]. The potential effects of several concomitant medications on quetiapine pharmacokinetics were studied [see Clinical Pharmacology (12.3 ) ] .

7.2 Effect of Quetiapine on Other Drugs Because of its potential for inducing hypotension, quetiapine extended-release tablets may enhance the effects of certain antihypertensive agents. Quetiapine extended-release tablets may antagonize the effects of levodopa and dopamine agonists. There are no clinically relevant pharmacokinetic interactions of quetiapine tablets on other drugs based on the CYP pathway. Quetiapine tablets and its metabolites are non-inhibitors of major metabolizing CYP’s (1A2, 2C9, 2C19, 2D6, and 3A4).